Mol Pain
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Extracellular regulated protein kinase (ERK) pathway activation in astrocytes and neurons has been reported to be critical for neuropathic pain development after chronic constriction injury. TGN-020 was found to be the most potent aquaporin 4 inhibitor among the agents studied. ⋯ Additionally, TGN-020 suppressed ERK phosphorylation in astrocytes and neurons after injury. The findings suggested that the analgesic effects of TGN-020 in neuropathic pain were mediated mainly by the downregulation of chronic constriction injury-induced astrocytic activation and inflammation, which is via the inhibition of ERK pathway in the spinal dorsal horn and dorsal root ganglion.
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Various small molecules act as neurotransmitters and orchestrate neural communication. Growing evidence suggests that not only classical neurotransmitters but also several small molecules, including amino acid derivatives, modulate synaptic transmission. As conditions of acute and chronic pain alter neuronal excitability in the nucleus accumbens, we hypothesized that small molecules released in the nucleus accumbens might play important roles in modulating the pain sensation. ⋯ We identified N-acetylaspartylglutamate as a potential pain modulator that is endogenously released in the nucleus accumbens. Infusion of N-acetylaspartylglutamate into the nucleus accumbens significantly attenuated the pain induced by the activation of sensory nerves through optical stimulation. These findings suggest that N-acetylaspartylglutamate released in the nucleus accumbens could modulate pain sensation.
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Background Diabetic neuropathy originating in distal lower extremities is associated with pain early in the disease course, overwhelming in the feet. However, the pathogenesis of diabetic neuropathy remains unclear. Macrophage migration inhibitory factor has been implicated in the onset of neuropathic pain and the development of diabetes. ⋯ Intriguingly, small interfering RNA-transfected knockdown of the migration inhibitory factor gene in methylglyoxal-treated skin keratinocytes increased expression of glyoxalase-I and intraepidermal nerve fibers in comparison with control small interfering RNA-transfected cells, which was decreased by induction of methylglyoxal. Conclusions Our findings suggest that migration inhibitory factor can aggravate diabetic neuropathy by suppressing glyoxalase-I and intraepidermal nerve fibers on the footpad skin lesions and provoke pain. Taken together, migration inhibitory factor might offer a pharmacological approach to alleviate pain syndromes in diabetic neuropathy.
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Grimace scales quantify characteristic facial expressions associated with spontaneous pain in rodents and other mammals. However, these scales have not been widely adopted largely because of the time and effort required for highly trained humans to manually score the images. Convoluted neural networks were recently developed that distinguish individual humans and objects in images. ⋯ In addition, we used a novel set of "pain" and "no pain" images to show that automated Mouse Grimace Scale scores are highly correlated with human scores (Pearson's r = 0.75). Moreover, the automated Mouse Grimace Scale classified a greater proportion of images as "pain" following laparotomy surgery when compared to animals receiving a sham surgery or a post-surgical analgesic. Together, these findings suggest that the automated Mouse Grimace Scale can eliminate the need for tedious human scoring of images and provide an objective and rapid way to quantify spontaneous pain and pain relief in mice.
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Background Neuropathic pain is observed in patients as chemotherapeutic oxaliplatin is used to treat metastatic digestive tumors; however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of pathophysiology of neuropathic pain. Since the midbrain periaqueductal gray is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines system of the periaqueductal gray in regulating mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin. ⋯ Our data further showed that the concentrations of gamma-aminobutyric acid were largely restored by blocking those pro-inflammatory cytokine receptors in periaqueductal gray of oxaliplatin rats; and mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin were attenuated. Stimulation of gamma-aminobutyric acid receptors in the periaqueductal gray also blunted neuropathic pain in oxaliplatin rats. Conclusions Our data suggest that the upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptor in the periaqueductal gray of oxaliplatin rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby contributes to the development of neuropathic pain after application of chemotherapeutic oxaliplatin.